This invention relates to glucuronic acid derivatives of opioid antagonists, and more particularly to the therapeutic use of such compounds in the treatment of localized symptoms with a minimum of systemic effects.
Opioid antagonists are a well-known class of drugs which can be used to prevent or promptly reverse the effects of morphine-like opioid agonists. See Goodman and Gilman's The Pharmacological Basis of Therapeutics, Sixth Edition, pp. 521-525. It is known that the opioid antagonist, naloxone, is converted by the human body to the glucuronide form, although no use for this form of naloxone has been found before the present invention. Of particular interest among the known opioid antagonists is nalmefene, which was first identified and claimed in U.S. Pat. No. 3,814,768 as 6-methylene-6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphine.
The constipating effect of opioids is the oldest known effect of these drugs. Indeed constipation is the most troubling side effect when opioid drugs are employed to relieve pain. Patients who require opioid analgesics to relieve pain on a chronic basis e.g. cancer victims, suffer severe constipation. Such constipation is also common among opioid addicts, and may even be a problem for those being given opioids on a short term basis, such as patients undergoing surgery.
Sudden withdrawal of opioid drugs following prolonged exposure provokes intestinal hypermotility and diarrhea results. This withdrawal phenomenon of hypermotility and diarrhea is also produced if an opioid antagonist is given after prolonged opioid administration. Thus the opioid can cause hypomotility and constipation, and withdrawal can cause the opposite effect of hypermotility and diarrhea. Hypomotility and hypermotility are dysmotilities at the extreme ends of the spectrum of intestinal motility. If an opioid antagonist were administered throughout the period of opioid exposure, intestinal dysmotility at both ends of the spectrum could be forestalled.
Attempts have been made to provide opioid antagonists that would relieve the constipating effect of exogenous opioids without antagonizing the analgesic effect. This is particularly important for chronic users or addicts since systemic antagonism can cause severe withdrawal symptoms mediated by the central nervous system. One class of compounds which has been investigated for this purpose are the quaternary ammonium derivatives of known narcotic antagonists (U.S. Pat. No. 4,176,187). The quaternary antagonists antagonize opioid induced intestinal hypomotility at lower doses than are required to antagonize opioid induced analgesia. The selective antagonism, i.e. more effective on intestinal hypomotility than on central nervous system analgesia, occurs because quaternary compounds are highly charged. The blood brain barrier impedes passage of highly charged drugs. Thus, the quaternary ammonium antagonists have more limited access to the opioid receptors in the central nervous system (CNS) that mediate analgesia than they do to the opioid receptors in the intestine that mediate hypomotility.
It is doubtful however that the quaternary ammonium antagonists will provide a practical solution to the clinical problem of the constipating effects of opioid analgesics. It has been known since the work of Eddy in 1933 (J. Pharmacol. Exp. Therap., 1967, 157: 185-195) that "quaternarization" was a means of directing opioids away from the CNS and toward the intestine. Yet no clinically useful quaternary opioid antagonist is available to patients. The failure of such a drug to emerge in therapeutics is likely related to the toxic effects on the autonomic nervous system that are known to occur with quaternary ammonium drugs.
In addition to relieving the constipating effects of exogenous opioids, the present invention is also directed to preventing endogenous opioids from exacerbating intestinal dysmotility of irritable bowel syndrome. In the last decade it's been discovered that the body produces its own opioids. The endogenous opioids are called endorphins and enkephalins. There is an abundance of endogenous opioids and opioid receptors in the intestinal tract. From the work of Kreek et al. (Lancet 1983 1: 262) it appears that such endogenous opioids contribute to intestinal dysmotility. Kreek et al. have shown that the opioid antagonist naloxone relieves constipation even though the patients have not been exposed to an exogenous opioid.
Irritable bowel syndrome is a form of intestinal dysmotility well known to gastroenterologists. The syndrome is characterized by pain as well as alternating constipation and diarrhea. The endogenous opioids may exacerbate the syndrome. The hypomotility and constipation phase of the syndrome could be the result of an excessive endogenous opioid influence, while the hypermotility and diarrhea could result from an abrupt cessation of endogenous opioid activity. In irritable bowel syndrome we believe that there is an exaggerated cyclic effect of the endogenous opioids on the intestines. During the upphase of the cycle the intestines can be immobilized and become physically dependent upon the endogenous opioids. During the down phase of the cycle the intestines can go into withdrawal, and thus become hypermotile and produce diarrhea. Pain can result from both constipation and diarrhea.
It appears then that a cycling auto-addiction and withdrawal is an important contributor to irritable bowel syndrome. Just as the continued presence of an opioid antagonist would prevent the addiction or physical dependence of the intestines to exogenous opioids, an antagonist should similarly prevent the exacerbating influence of cycling endogenous opioids on the intestine.